School of Pharmacy and Pharmaceutical Scienceshttp://hdl.handle.net/2262/74
School of Pharmacy and Pharmaceutical Sciences

2019-03-21T18:08:44ZInvestigating mechanisms of anti-cancer drug resistance in breast cancer cells and extracellular vesicleshttp://hdl.handle.net/2262/86081
Investigating mechanisms of anti-cancer drug resistance in breast cancer cells and extracellular vesicles
LOWRY, MICHELLE
Breast cancer is the most common female cancer diagnosed worldwide. In 2018 alone, there were over 2 million new breast cancer cases diagnosed. In Ireland, breast cancer is the most commonly diagnosed cancer in women. In Ireland, breast cancer accounts for approximately 3,141 cases each year. Of which, a subtype of breast cancer called HER2overexpressing/HER2+ breast cancer accounts for 15-25% of breast cancers. This subtype of breast cancer has a genetic mutation that causes the cancer cells to produce larger amounts of the protein called HER2. HER2 promotes the growth of cancer cells and patients with this type of breast cancer often have high levels of metastasis, or spread of the cancer to other organs. Unfortunately, like with many cancer therapies, some patients do not respond to anti-HER2 therapies, i.e. patients are or become resistant to therapy. Some patient’s tumours will immediately not respond to therapy (innate resistance), whereas, other patient tumour’s will initially respond well to the therapies but overtime the cancer cells can find ways to overcome the effects of the therapy i.e. the tumours become resistant to therapy (adaptive resistance). Innate and adaptive resistance to anticancer therapies are the main reasons that anti-cancer drugs fail in the clinic. It is imperative that we investigate the mechanisms of drug resistance, find ways to overcome this resistance and find ways to predict and/or find predictive biomarkers.
The focus of this PhD is on a drug that stops HER2 working, it is called Neratinib. Neratinib prevents HER2 functioning and in doing so it can prevent cancer cell growth. Neratinib was approved by the Food and Drug Administration (FDA) in July 2017. Neratinib is showing promise in the clinic but, like most therapies, the issue of resistance prevails. We have developed HER2+ breast cancer cell lines that are resistant to neratinib i.e. neratinib does not kill them. When we compared cells that die from neratinib with cells that do not die after neratinib treatment, we found that the resistant cell lines produce very large amounts of a protein called PROTEIN X. The cells that are sensitive to neratinib or the cells that die after neratinib treatment, do not produce large amounts of PROTEIN X. We believe that PROTEIN X acts like a defence system for breast cancer cells.
This discoveries made in this PhD may be imperative to overcoming neratinib resistance in the future, for predicting response to therapy (so that patients can be stratified into those who are likely versus unlikely to respond to HER-targeting), and so improving the survival rates of patients treated with neratinib and other HER2-targeted therapies. We also believe that PROTEIN X has potential as a predictive biomarker for HER2 therapies such as lapatinib and trastuzumab, but most notably for neratinib. PROTEIN X may be an important marker for future therapeutic decisions in clinics.
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2019-01-01T00:00:00ZSynthesis of Tubulin Inhibitors with Variable Molecular Hinges for the Attachment of Aminopeptidase N Targeting Moietieshttp://hdl.handle.net/2262/86077
Synthesis of Tubulin Inhibitors with Variable Molecular Hinges for the Attachment of Aminopeptidase N Targeting Moieties
ANWAR, ZEESHAN
This thesis includes synthesis of various tubulin binding agents and their incorporation in to novel dual acting hybrids, which along with the tubulin inhibition also exhibit aminopeptidase N (APN) inhibition activities.
This thesis begins with an overview of the process of angiogenesis, the tumour vasculature network and the differences between tumor and normal vascular systems. The two main therapeutic approaches, by targeting angiogenesis and the newly formed vascular network, are also discussed. Moreover the concept of targeted therapy utilising the multifunctional enzymatic receptor APN is also presented along with various different hybrid drug approaches. The first chapter closes with a brief overview of the principal aims of the project.
The initial focus of chapter 2 was the synthesis of 4-arylcoumarin derivatives having tetramethoxy arrangement. The work described in this chapter then progressed towards thionation of the carbonyl moiety at position 2 as this group can be replaced with a series of incoming nucleophiles unlike its carbonyl counterpart. Having successfully completed this transformation a series of suitable linker units were attached to this position primarily centred around oxime and hydrazone derivatives. Introduction of alcohol, aldehyde, carboxylic acid and amine functionalities at position 3 of the 4-arylcoumarins then follows. Significant emphasis in the later part of the chapter involves the double functionalisation of the 4-arylcoumarin with a phenolic group on the A-ring and an aniline group on the C-ring, as the chapter closes with an evaluation of the newly synthesised compounds as inhibitors of tubulin polymerisation.
The synthesis of the phenstatin series in chapter 3 focuses on introducing additional hinges onto their structure principally based around a catechol structure on the A-ring while the B-ring was represented by a substituted aniline or phenol ring. This chapter also discusses the synthesis of phenstatin-like compounds, having a propanal side chain, an ideal functional group for both derivatisation and for conjugation of APN targeting moieties. These compounds were then evaluated as inhibitors of tubulin polymerisation.
Chapter 4 centres on exploring the concept of hybrid drug therapy and employing it for the delivery of different tubulin binding agents whose synthesis is described in chapters 2 and 3. This chapter involves the incorporation of APN targeting moieties onto the tubulin binding agents for the purpose of creating hybrid drugs that have the capacity to inhibit both APN and tubulin polymerisation.
Chapter 5 presents the experimental procedures used in the synthesis, characterisation of compounds as well as the procedures utilised for APN inhibition and tubulin polymerisation assay.
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2019-01-01T00:00:00ZElectronic Counselling for Oral Anticoagulant Patientshttp://hdl.handle.net/2262/86067
Electronic Counselling for Oral Anticoagulant Patients
KADI, KHULUD TARIQ B
Education is an essential part of care for patients taking oral anticoagulants. However, it may be
time-consuming for health care providers and overwhelming for patients, and hence sometimes
suboptimal. Technology-based education programs have the potential to overcome some of the
problems relating to patient education and thus help to minimize therapy complications and
improve clinical outcomes. The principal purposes of this study were to identify and evaluate
research on electronic education interventions for warfarin patients, and to create and pilot
electronic education programs for warfarin and DOAC patients.
Chapter 1 provides general background information on coagulation, anticoagulants and patient
education.
Chapter 2 describes a systematic review, to our knowledge the first to evaluate technologybased educational interventions for warfarin patients.
Searches were conducted of the Cochrane Library (CENTRAL), Ovid (MEDLINE), PubMed, CINAHL
Plus (EBSCOhost), ERIC ProQuest, and Web of Science databases, as well as of US and EU clinical
trials databases, for randomized controlled trials evaluating the effect of any electronic
education intervention alone or in combination with other self-management techniques, in
warfarin patients. The searches included studies published in English without date restrictions.
Manual searches of reference lists in relevant publications were also conducted. All identified
references were screened for inclusion within Endnote software. The Cochrane Collaboration?s
Review Manager 5.3 (Rev Man 2014) software was then used for further data extraction and
analysis. Risk of bias was assessed using the Cochrane ?Risk of bias? tool.
Three randomized control trials and one ongoing study were identified. While they showed
positive effects for electronic education of warfarin patients, the small size and heterogeneous
nature of the identified studies mean the findings are limited in their value, and meta-analysis
was not possible. More adequately powered, good quality, randomized, controlled studies are
required in this area.
Chapter 3 describes the development and piloting of an electronic tool to educate and assess
patients? knowledge regarding their warfarin therapy. The tool was developed using Articulate
360 software and consisted of three main sections: a pre-education knowledge test (a previously
validated anticoagulant knowledge test), an education section, and repetition of the knowledge
test. It was piloted in the community pharmacy on English-speaking adult patients receiving
warfarin who could use a suitable electronic device. A total of 56 patients participated in the pilot. 35/56 (62.5%) passed the knowledge test before
the education program and this showed a statistically significant increase to 51/56 (91.1%)
after the education program, demonstrating the utility of the tool in the short-term. Feedback
to enhance the electronic tool was also received. The results of this pilot have laid the
foundation for a future more comprehensive study incorporating long term follow up and a
wider range of outcome measures.
Chapter 4 concerns the development and piloting of an electronic education program for
patients taking direct-acting oral anticoagulants (DOACs), which are increasingly being
prescribed owing to their advantages over warfarin: They can be given in fixed doses, have
fewer interactions with food or other drugs, a wide therapeutic window and do not require
monitoring as closely as warfarin. As for the warfarin education tool, the DOAC program
comprised educational material preceded and followed by knowledge tests. However, in this
case the education component took the form of a dialogue between a pharmacist and patient,
with points of interactivity where the patient selected material relevant to the DOAC he/she
had been prescribed. Baseline adherence was established through the incorporation of the
Morisky 8-item medication adherence scale (MMAS-8) into the program before the education
component. The pre- and post-education knowledge test comprised relevant questions from
the same anticoagulation knowledge test as that used in the warfarin education program.
The program was evaluated in community pharmacies and by pharmacists in the pharmacistled outpatient anticoagulation clinic of a major Dublin hospital. Eligible patients were Englishspeaking adults who were capable of using appropriate electronic devices.
A total of 53 patients enrolled in the pilot. 43/53 (81.1%) patients passed the test before the
education program, and this showed a significant increase to 50/53 (94.3%) after education. In
the MMAS-8 item questionnaire only 4 patients showed a low level of self-reported baseline
adherence, 23 patients had a medium level of adherence, and 26 patients had a high
adherence level.
This pilot study confirmed that the tools were capable of being used in the workplace
environment and of enhancing patient knowledge in the short term. Feedback was received on
potential improvements, in particular to enhance the personalization of the education
experience for individual patients, enabling future work to assess a refined intervention in a
larger and longer duration randomized controlled trial with more comprehensive outcome
measures.
Chapter 5 explores the overall findings, and sets out the future work that can build upon the
studies described here.
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2019-01-01T00:00:00ZThe optimisation, characterisation and platelet compatibility of polymeric nanocarriers loaded with NSAIDshttp://hdl.handle.net/2262/85327
The optimisation, characterisation and platelet compatibility of polymeric nanocarriers loaded with NSAIDs
Crean, Joanne
There is a constant drive towards improving global health by continuously enhancing the quality of drugs available and the systems to deliver these drugs efficiently in order to treat disease. This thesis focused on the development of two types of biodegradable polymeric nanocarriers (NCs), poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) and hyaluronic acid:chitosan (HA:CS) polyelectrolyte complex nanoparticles (PECNs) loaded with two hydrophobic model drugs with anti-platelet action, indometacin (IND) and ketoprofen (KET). PLGA NPs were a hydrophobic system formed by an emulsion-solvent diffusion technique and HA:CS PECNs, which were hydrophilic systems formed based on electrostatic interactions between two polymers.
2014-01-01T00:00:00Z